Aspirin potentiates celecoxib-induced growth inhibition and apoptosis in human non-small cell lung cancer by targeting GRP78 activity

Abstract

Background: Aspirin has recently emerged as an anticancer drug, but its therapeutic effect on lung cancer has been rarely reported, and the mechanism of action is still unclear. Long-term use of celecoxib in large doses causes serious side effects, and it is necessary to explore better ways to achieve curative effects. In this study, we evaluated the synergistic anticancer effects of celecoxib and aspirin in non-small cell lung cancer (NSCLC) cells. Methods: In vitro, we evaluated the combined effects of celecoxib (40 μM) and aspirin (8 mM) on cell apoptosis, cell cycle distribution, cell proliferation, cell migration and signaling pathways. Furthermore, the effect of aspirin (100 mg/kg body weight) and celecoxib (50 mg/kg body weight) on the growth of xenograft tumors was explored in vivo. Results: Our data suggest that cancer sensitivity to combined therapy using low concentrations of celecoxib and aspirin was higher than that of celecoxib or aspirin alone. Further research showed that the anti-tumor effect of celecoxib combined with aspirin was mainly produced by activating caspase-9/caspase-3, arresting cell cycle and inhibiting the ERK-MAPK signaling pathway. In addition, celecoxib alone or in combination with aspirin inhibited the migration and invasion of NSCLC cells by inhibiting MMP-9 and MMP-2 activity levels. Moreover, we identified GRP78 as a target protein of aspirin in NSCLC cells. Aspirin induced an endoplasmic reticulum stress response by inhibiting GRP78 activity. Furthermore, combination therapy also exhibited a better inhibitory effect on tumor growth in vivo. Conclusions: Our study provides a rationale for further detailed preclinical and potential clinical studies of the combination of celecoxib and aspirin for NSCLC therapy.

Peroxidase from foxtail millet bran exerts anti-colorectal cancer activity via targeting cell-surface GRP78 to inactivate STAT3 pathway

“…Hence, the ATPase catalytic activity was necessary for the anti-apoptotic function of GRP78 through preventing caspase activation 42 . For example, some compounds, such as EGCG, honokiol and aspirin, increase the chemotoxic sensibility toward cancer cells by directly binding to GRP78-NBD to inhibit the ATPase activity 43 , 44 , 45 . Excitedly, in our current study, the subsequent anti-tumor activity assay demonstrated that in CRC LS174-T cells, overexpressed GRP78-N500 truncation (including NBD and membrane translocation sequences) could significantly increase the chemotoxic sensitivity of FMBP to LS174-T cells, accompanied by the elevation of ROS production and the apoptosis rate, as well as the reduction of cell viability radio ( Fig.…”

Maprotiline Suppresses Cholesterol Biosynthesis and Hepatocellular Carcinoma Progression Through Direct Targeting of CRABP1

“…Reinterpretation of drug efficacy will avoid the high clinical failure rate caused by ADMET, which reduces the R&D cost and shortens the time of manufacture. Celecoxib was initially approved by the Food and Drug Administration (FDA) as an analgesic, anti-inflammatory and antipyretic drug, followed by a large amount of preclinical evidence showing that celecoxib has a strong killing effect on cancer ( Li et al, 2018 ; Zuo et al, 2018 ; Liu et al, 2019 ; Zhang et al, 2020 ). Therefore, the anticancer activity of maprotiline will be promising for development as a new kind of HCC treatment drug.…”

The Antitumor Effect of TPD52L2 Silencing on Oxaliplatin-Resistant Gastric Carcinoma Is Related to Endoplasmic Reticulum Stress In Vitro

“…Moreover, GRP78 is considered to be the principal ER stress biomarker. CHOP is an ER-stress-induced apoptosis marker; PERK and IRE1α are ER stress sensor proteins [12][13][14][15][16]. Whether the ER stress trigger is related to the downregulation of TPD52L2 expression in OXA-resistant gastric cells remains to be clarified.…”